Pancreatic B cell death leads to profound insulin deficiency, hyperglycemia and type I diabetes. Neogenesis, the differentiation of B cells from non-B cells, could be important to islet cell re-population in neonates and adult mice. The PI has characterized the phenotype of embryonic islet progenitor cells and sought to elucidate whether similar cells appeared in adults. The findings suggest that, during development the glucagon(a), insulin(B), somatostatin (delta) pancreatic polypeptide (PP) cells were produced by multipotential stem cells. Common to these cells is coexpression of the homeodomain protein, PDX-1 (pancreas duodenum homeobox gene-1). To determine whether adult pancreas contained B stem cells, pancreatic tissues of adult mice rendered diabetic by streptozotocin (SZ) were examined. SZ-treatment induced differentiation in islets of PDX-1+ precursor cells that initiated insulin (IN) synthesis. The number of newly formed B cells in adult mice was low and the animals remained severely hyperglycemic. The PI tested the hypothesis that normoglycemia had a beneficial effect on islet cell regeneration and preliminary experiments revealed a striking increase in B cell neogenesis in adult SZ-treated mice rendered normoglycemic by exogenous insulin. The PI will determine whether B cell neogenesis is due to a specific effect of SZ or if it also occurs in Type I diabetes models i.e. the NOD mouse. It will also determine whether the initial effect of insulin- induced normoglycemia is the enhancement of B cell differentiation. Finally, it will be determined whether sustained normoglycemia promotes the survival of the newly differentiated insulin cells and whether these cells are able to maintain normal blood glucose levels following interpretation of the therapeutic insulin treatment. These studies raise the possibility that a significant number of B cells will reform in diabetic mice rendered euglycemic by exogenously administered IN. Perhaps sustained homoglycemia will promote their survival an maturation. It is possible that fully differentiated B-cells will suffice to maintain glucose homeostasis. These results have implications for the restoration of B cells and the achievement of normoglycemia in type I diabetic patients.